Aryl-pyrimidine-alkanoic acid derivatives



United States Patent 3,502,673 ARYL-PYRIMIDINE-ALKANOIC ACID DERIVATIVESWalter Hepworth and Thomas Walton Thompson, Macclesfield, England,assignors to Imperial Chemical Industries Limited, London, England, acorporation of Great Britain No Drawing. Filed May 16, 1967, Ser. No.638,726 Claims priority, application Great Britain, June 17, 1966,27,083/66 Int. Cl. C07d 51/36; A61k 27/00 US. Cl. 260251 Claims ABSTRACTOF THE DISCLOSURE This invention relates to new pyrimidine derivativeswhich have useful anti-inflammatory, analgesic and antipyretic activity.

According to the invention we provide pyrimidine derivatives of theformula:

W C N Y wherein W stands for hydrogen or an alkyl radical of not morethan four carbon atoms, X stands for hydrogen, an alkyl or alkoxyradical of not more than 4 carbon atoms, or a halogen atom, Y stands forthe phenyl or benzyl radical, either of which may optionally besubstituted by one or two halogen atoms or by the trifluoromethylradical, and Z stands for a radical of the formula CR R R wherein Rstands for hydrogen, an alkyl radical of not more than three carbonatoms, or a chlorine or bromine atom, R stands for hydrogen, an alkylradical of not more than three carbon atoms, an alkoxycarbonyl radical,or a chlorine or bromine atom, and R stands for a radical of the formulaCO R or CONHR wherein R stands for hydrogen or an alkyl,dialkylaminoalkyl or benzyl radical, and R stands for hydrogen or anamino, dialkylaminoalkyl, alkoxycarbonylalkyl or carboxyalkyl radical,and the salts thereof, provided that the Y and Z radicals are not linkedto adjacent carbon atoms in the pyrimidine nucleus, and excluding ethyl4-chloro-2-phenylpyrimid-S-ylacetate, ethyl Z-phenylpyrimid-5-ylacetate,Z-phenylpyrimid-S-ylacetic acid, ethyl 2-benzylpyrimid-5- ylacetate andethyl 4-methyl-2-phenylp-yrimid-S-yIacetate.

The pyrimidine nucleus is numbered as follows:

As stated above, in the pyrimidine derivatives of this invention the Yand Z radicals are not linked to adjacent carbon atoms in the pyrimidinenucleus. That is to say, when Y is linked to position 4 to 6, Z is notlinked to posi ICC tion 5 ,and when Z is linked to position 4 or 6, Y isnot linked to position 5. Accordingly, it is to be understood thatthroughout this specification the definitions of the final products andintermediates do not include compounds wherein the Y and Z radicals, orcorresponding radicals, are linked to adjacent carbon atoms in thepyrimidine nucleus.

As a suitable value for W when it stands for an alkyl radical of notmore than 4 carbon atoms there may be mentioned, for example, the methylradical.

As a suitable value for X when it stands for an alkyl or alkoxy radicalof not more than 4 carbon atoms there may be mentioned, for example, themethyl, methoxy or ethoxy radical. As a suitable value for X when itstands for a halogen atom there may be mentioned, for example, achlorine or bromine atom.

The halogen substituent(s) which may optionally be present in radical Ymay, for example, be selected from fluorine, chlorine and bromine atoms.

One particular embodiment of this invention consists of said pyrimidinederivatives wherein Y is a phenyl or benzyl radical which is substitutedby one or two halogen atoms or the trifluoromethyl radical.

As a suitable value for R or R when either stands for an alkyl radicalof not more than 3 carbon atoms there may be mentioned, for example, themethyl radical. As a suitable value for R when it stands for analkoxycarbonyl radical there may be mentioned, for example, analkoxycarbonyl radical of not more than 6 carbon atoms, for example, theethoxycarbonyl radical.

As a suitable value for R when it stands for an alkyl radical there maybe mentioned, for example, an alkyl radical of not more than 6 carbonatoms, for example the methyl, ethyl or isopropyl radical. As a suitablevalue for R or R when it stands for a dialkylaminoalkyl radical theremay be mentioned for example, a dialkylaminoalkyl radical of not morethan 8 carbon atoms, for example the fl-diethylaminoethyl radical. As asuitable value for R when it stands for an alkoxycarbonylalkyl radicalthere may be mentioned, for example, an alkoxycarbonylalkyl radical ofnot more than 8 carbon atoms, for examle the ethoxycarbonylmethylradical. As a suitable value for R when it stands for a carboxyalkylradical there may be mentioned, for example, a carboxyalkyl radical ofnot more than 6 carbon atoms, for example, the carboxymethyl radical.

As suitable salts'in the case while Z stands for an ester or amide groupthere may be mentioned pharmaceutically-acceptable acid-addition salts,for example a hydrochloride or tartrate. In the case where R stands forthe carboxy radical (CO H), suitable salts are salts with alkali metalsor alkaline earth metals, for example sodium or calcium salts, oraluminium or ammonium salts, or salts with pharmaceutically-acceptableorganic bases.

Preferred pyrimidine derivatives of this invention are methyl2-p-chlorophenyl-6-methoxypyrimid-4-ylacetate, diethyl2-(2-p-chlorophenyl-6-methoxypyrimid-4-yl)malonate,2-p-chlorophenyl-6-methoxy-4-methylpyrlmid-5-ylacetic acid, and methyla-(2-chlorophenyl-6-methoxypyrimid-4-yl)propionate.

According to a further feature of the invention we provide a process forthe manufacture of pyrimidine derivatives of the formula:

provided that neither R nor R stands for a chlorine or bromine atom, andHal stands for a halogen atom in the 2-, 4- or 6-position, whichcomprises reacting the corresponding hydroxypyrimidine derivative of theformula:

OH 63 N Y wherein W, Y and Z have the meanings stated above and thehydroxy radical is in the 2-, 4- or 6-position, with a halogenatingagent as defined hereinafter.

As a suitable value for Hal there may be mentioned, for example, achlorine or bromine atom. It is to be understood that in thisspecification the expression halogenating agent means any agent which isknown to convert a hydroxy derivative into the corresponding halogenoderivative, for example phosphorus oxychloride or phosphorus oxybromide.The reaction may be carried out in a diluent or solvent, for examplebenzene, and in the presence of an acid-binding agent, for example N,N-diethylaniline. The reaction may be accelerated or completed by theapplication of heat. The hydroxy-pyrimidine derivatives used as startingmaterials may be obtained in conventional manner by the interaction ofthe appropriate amidine and the appropriate keto ester.

According to a further feature of the invention We provide a process forthe manufacture of alkoxy-pyrimidine derivatives of the formula:

OAlk

wherein W, Y and Z have the meanings stated above, provided that neitherR nor R stands for a chlorine or bromine atom, and OAlk stands for analkoxy radical in the 2-, 4- or 6-position, which comprises reacting ahalogenopyrimidine derivative of the formula:

NJ W wherein W, Y, Z and Hal have the meanings stated above, with theappropriate alkali metal alkoxide.

The reaction may be carried out in a diluent or solvent, for example thealkanol from which the alkali metal alkoxide is derived, or an aromatichydrocarbon solvent, for example xylene. The interaction may beaccelerated or completed by the application of heat. It is to beunderstood that, in the case where Z in the starting material stands foran ester radical derived from a different alcohol than that from whichthe alkoxide reactant is derived, in some cases the product is the esterderived from the alkanol corresponding to the alkoxide. Thus, forexample, if the starting material is an ethyl ester, the alkoxide issodium methoxide, and the solvent is methanol, the product may beobtained as the corresponding methyl ester.

According to a further feature of the invention we provide a process forthe manufacture of compounds of the formula:

wherein W. Y and Z have the meanings stated above, provided that neitherR nor R stands for a chlorine or bromine atom, and OAlk' stands for analkoxy radical 4 in the 2-, 4-, 5- or 6-position, which comprisesreacting a hydroxypyrimidine derivative of the formula:

provide a process for the manufacture of pyrimidine derivatives of theformula:

H C w N Y wherein W, Y and Z have the meanings stated above providedthat neither R nor R stands for a chlorine or bromine atom, whichcomprises dehalogenating a halogeno-pyrimidine derivative of theformula:

Hal W i Y wherein W, Y and Z have the meanings stated above and Halstands for a halogen atom in the 2-, 4-, 5- or 6- position.

As a suitable dehalogenating agent there may be mentioned, for example,zinc dust. The reaction may be carried out in a diluent or solvent, forexample aqueous dioxan, and it may be accelerated or completed by theapplication of heat.

According to a further feature of the invention we provide a process forthe manufacture of compounds of the formula:

R R tOOzH wherein W, X, Y, R and R have the meaning stated aboveprovided that R does not stand for a chlorine or bromine atom and R doesnot stand for a chlorine or bromine atom or an alkoxycarbonyl radical,which comprises hydrolysing a compound of the formula:

CR RZAQ wherein W, X, Y, R and R have the meanings stated above, and Acstands for the cyano (CN) or carbamoyl (CONH radical or a radical of theformula wherein R stands for an alkyl radical or the phenyl or benzylradical. As a suitable hydrolytic agent there may be mentioned aninorganic base, for example an alkali metal hydroxide, for examplesodium hydroxide, or an acid, for example an inorganic acid, for examplehydrochloric or sulphuric acid. The hydrolysis is carried out in thepresence of water, and an organic solvent, for example ethanol, mayoptionally be present. The hydrolysis may be accelerated or completed bythe application of heat.

According to a further feature of the invention we provide a process forthe manufacture of compounds of the formula:

wherein W, X, Y, R and R have the meanings stated above provided that Rdoes not stand for a chlorine or bromine atom, and Alk stands for analkyl radical of not more than 3 carbon atoms, which comprisesa-alkylating a compound of the formula:

W i N Y H- (ll-R wherein W, X and Y have the meanings stated above, Rand .R stand for hydrogen or an alkyl radical of not more than 3 carbonatoms, and R stands for hydrogen or an amino or dialkylaminoalkylradical, and the salts thereof, which comprises reacting a compound ofthe formula W l=x N Y IIURQCOZR wherein W, X, Y, R R and R have themeanings stated above, with a compound of the formula R NH wherein R hasthe meaning stated above. As a suitable value for R when it stands foran alkyl radical there may be mentioned, for example, an alkyl radicalof not more than 4 carbon atoms, for example the methyl or ethylradical. The reaction may be carried out in a diluent or solvent, forexample methanol, and it may be accelerated or completed by theapplication of heat.

According to a further feature of the invention we provide a process forthe manufacture of pyrimidine derivatives of the formula:

W C X N Y OR RACONHR' wherein W, X, Y, R and R have the meanings statedabove provided that neither R nor R stands for a chlorine or bromineatom, and R stands for an alkoxycarbonylalkyl or dialkylaminoalkylradical, and the salts thereof, which comprises reacting a compound ofthe formula:

CR R -COzH wherein W, X, R and R have the meanings stated above, with anamine of the formula R NH wherein R has the meaning stated above, in thepresence of dicyclohexylcarbodiimide. The reaction may be carried out ina diluent or solvent, for example dry chloroform, at a temperature ofabout 0 C. The products in which R stands for an alkoxycarbonylalkylradical may be hydrolysed by reaction with a base, for example an alkalimetal hydroxide, to give the corresponding compounds in which R standsfor a carboxyalkyl radical.

According to a further feature of the invention we provide a process forthe manufacture of esters of the formula RIRZ- 00212 wherein W, X and Yhave the meanings stated above, R and R stand for hydrogen or an alkylradical of not more than 3 carbon atoms, and R stands for an alkyl,dialkylaminoalkyl or benzyl radical, which comprises reacting a salt ofthe formula:

W C X N Y mula:

w 5 N Y wherein W, X and Y have the meanings stated above, R and R standfor hydrogen or an alkyl radical of not more than 3 carbon atoms, and Rstands for an alkyl, dialkylaminoalkyl or benzyl radical, which comrises reacting the appropriate carboxylic acid with a compound of theformula :R OH, wherein R has the meaning stated above, in the presenceof an inorganic acid, for example sulphuric or hydrochloric acid, ordicyclohexylcarbodiimide. The reaction may be accelerated or completedby the application of heat, and it may optionally be carried out in thepresence of an inert diluent or solvent.

According to a further feature of the invention we provide a process forthe manufacture of esters of the formula w X N Y 7 wherein W, X and Yhave the meanings stated above, R and R stand for hydrogen or an alkylradical of not more than 3 carbon atoms; and R stands for an alkylradical of more than 2 carbon atoms, or a dialkylaminoaikyl or benzylradical, which comprises reacting an ester of the formula:

wherein W, X,; Y, R and R have the meanings stated above, and It standsfor or 1, with an aluminum derivative of the formula Al9R wherein R hasthe meaning stated, above. The reaction may be carried out in thepresence of an excess of the alcohol of the. formula R H, wherein R hasthe meaning stated above, and/or in the presence of an inert solvent,for example an aromatic hydrocarbon solvent for example toluene. Thereaction may be accelerated or completed by the application of heat. a1i According to a further feature of the invention we provide a processfor the manufacture of the pyrimidine derivativesof the inventionwherein R stands for a chlorine or bromine atom and R stands forhydrogen, angalkyl radical of not more than 3 carbon atoms, or analkoxycarbonyl radical, or wherein R and R are selected from chlorineand bromine atoms, which comprises reacting the corresponding compoundwherein R or R and R stands or stand for hydrogen, with chlorine orbromine. The reaction may be carried out the presence of an alkali metalacetate, for example sodium acetate, and/or glacial acetic acid.

According to a further feature of the invention we provide a process forthe manufacture of compounds: of the formula: V a

if w 11 X \N Y CRERZCONH:

wherein W, X and Y have the meanings stated above, and R and R stand forhydrogen or an alkyl radical of not more than 3 carbon atoms, whichcomprises hydrolysing the corresponding nitrile of the formula:

ca mer;

wherein W, X and Y have the meanings stated above, R and R stand forhydrogen or an alkyl radical of not more than 3 carbon atoms, and Rstands' for an alkyl or benzyl radical, which comprises reacting anitrile of the formula: T W

eR R oN wherein W, X, Y, R and R have the meanings stated above, or thecorresponding amide (CR R C0NH and a compound of the formula R OH,wherein R has the meaning stated above, under acidic conditions. Theacidic conditions may be provided by the presence of an inorganic acid,for example sulphuric or hydrochloric acid. The reaction may beaccelerated or completed by the application of heat. 7

According to a further feature of the invention we provide a process forthe manufacture of pyrimidine derivatives of the formula: V

wherein W, X and Y have the meanings stated abfive, R stands forhydrogen or an alkyl radical of not more than 3 carbon atoms, and Rstands for an alkyl radica provided that the CR (CO R group is notlinked to the 5-position of the pyrimidine nucleus, which comprisesreacting sodium or potassium, or a hydride, amide or alkoxide thereof,with a carbonate of the formula CO.(OR wherein R has the meaning statedabove, and a compound of the formula: Y

onmoozn wherein W, X and Y have the'meanings stated above, and R standsfor hydrogen or an alkyl radical of not more than 3 carbon atoms,,butprovided that the CHR .CO H group is not linked to the 5-position of thepyrimidine nucleus, and salts thereof, which comprises reacting acompound of the formula:

i cnwconwr wherein W, X, Y and R have the meanings stated above, Rstandsifor an alkyl radical, and the -CR (CO R group is not linked tothe S-positien of the pyrimidine nucleus, with an inorganicdiase in thepresence of water, and under the influence of heat. As a suitable basethere may be mentioned, for :example; an alkali metal hydroxide. Thereaction may be carried out in the presence of an organic solvent, forexample methanol.

According to a further feature of the invention we provide a process forthe manufacture of pyrimidine derivatives of the formula:

wherein Y has the meaning stated above, and R stands for hydrogen or analkyl radical of not more than 3 carbon atoms, which comprises reactinga compound of the formula:

wherein R has the meaning stated above, with a compound of the formula:

Y ooH-o=oHNR2 wherein Y has the meaning stated above and R stands for analkyl radical. As a suitable value for R there may be mentioned, forexample, an alkyl radical of not more than four carbon atoms, forexample the methyl radical. The reaction may be carried out in anorganic solvent, for example ethanol, and it may be accelerated orcompleted by the application of heat.

According to a further feature of the invention we providepharmaceutical compositions comprising at least one pyrimidinederivative of the formula:

W N Y herein W, X, Y and Z have the meanings stated above provided thatthe Y and Z radicals are not linked to adjacent carbon atoms in thepyrimidine nucleus, or a salt thereof, and an inert,pharmaceutically-acceptable diluent or carrier.

As suitable pharmaceutical compositions there may be mentioned, forexample, tablets, pills, capsules, non-sterile aqueous or non-aqueoussolutions or suspensions, sterile injectable aqueous or non-aqueoussolutions or suspensions, creams, lotions or ointments. Thesecompositions may be obtained in conventional manner using conventionalexcipients.

The invention is illustrated by the following examples in which theparts are by weight.

EXAMPLE 1 Dry nitrogen is bubbled through a mixture of 280 parts ofphosphorus oxychloride and 14.35 parts of N,N-di ethylaniline for 30minutes. 28.2 parts of ethyl2-pchlorophenyl-6-hydroxypyrimid-4-ylacetate are added and the mixtureis heated under reflux for 30 minutes, by which time evolution ofhydrogen chloride has ceased. The excess of phosphorus oxychloride isremoved by evaporation under reduced pressure. The residual oil istriturated with ice-water and the solid formed is extracted into 300parts of ether. The ethereal solution is washed successively with 50parts of water, 50 parts of saturated sodium bicarbonate solution, and25 parts of water, and is then dried with anhydrous magnesium sulphateand evaporated to dryness. The residue is crystallised from petroleumether (B.P. 60-80 C.). There is thus obtained ethyl6-chloro-2-p-chlorophenylpyrimid-4-ylacetate, M.P. 87-88" C.

The ethyl 2-p-chlorophenyl-6-hydroxypyrimid-4-ylacetate used as startingmaterial may be obtained as follows:

19.1 parts of p-chlorobenzamidine hydrochloride are dissolved in 300parts of Water, and the solution is stirred and to it is added, atambient temperature, a solution of 10.4 parts of potassium carbonate in20 parts of '10 water. 10.1 parts of diethyl acetonedicarboxylate areadded, and ethanol is then added dropwise with stirring until completedissolution is achieved. The mixture is stirred at ambient temperaturefor 18 hours and then filtered. Both the solid residue and the filtrateare retained. The solvent is evaporated under reduced pressure from thefiltrate, the residue is cooled, and the resulting mixture is filtered.The two solid residues are combined and dissolved in a mixture of 25parts of methanol and 75 parts of chloroform. The solution is passedthrough a column of 350 parts of magnesia-silica gel. The column iseluted with 1500 parts of a 5:95 v./v. methanol:chloro form mixture. Thesolvent is evaporated under reduced pressure from the eluate and thereis thus obtained ethyl 2-p-chlorophenyl 6 hydroxypyrimid 4 ylacetate,M.P. 169-171 C.

EXAMPLE 2 The process described in Example 1 for the preparation of the6-chloropyrimidine derivative is repeated except that 10.7 parts ofethyl 6-hydroxy-2-phenylpyrimid-5-ylacetate, 107 parts of phosphorusoxychloride, and 6.2 parts of N,N-diethylaniline are used. The productis crystallised from ethanol with cooling to 40 C. There is thusobtained ethyl 6-chloro-2-phenylpyrirnid-4-ylacetate, M.P. 41 C.

The ethyl 6-hydroxy-2-phenylpyrimid-4-ylacetate used as startingmaterial may be obtained as follows:

31.3 parts of benzamidine hydrochloride are dissolved in 300 parts ofWater, and a solution of 27.6 parts of potassium carbonate in 30 partsof water is added, with stirring, at ambient temperature. 40.4 parts ofdiethyl acetonedicarboxylate are added and ethanol is then addeddropwise with stirring until complete dissolution is achieved. Themixture is stirred at ambient temperature for 48 hours and thenfiltered. Both the solid residue and the filtrate are retained. The pHof the filtrate is adjusted to 6 by the addition of dilute acetic acid,whereupon a solid precipitates. This solid is collected by filtration,and the two solids are combined and crystallised from ethanol. There isthus obtained ethyl 6-hydroxy-2-phenylpyrimid-4-ylacetate, M.P. 156-158C.

EXAMPLE 3 0.9 part of sodium is dissolved in 50 parts of dry methanol,and a solution of 6 parts of ethyl 6-chloro-2-p-chlorophenylpyrimid-4-ylacetate in 150 parts of dry methanol isadded dropwise at 15 C. The mixture is stirred for 18 hours at ambienttemperature, and water is then added until precipitation is complete.The mixture is filtered; both the solid residue and the filtrate beingretained. The solid residue is crystallised from ethanol and there isthus obtained methyl 2-p-chlorophenyl-6- methoxypyrimid-4-ylacetate,M.P. 78-80 C. The filtrate is acidified with 2 N hydrochloric acid, andthe resulting mixture is filtered. There is thus obtained, as solidresidue, 2-p-chlorophenyl-6-methoxypyrimid-4-ylacetic acid M.P. 123 C.with decomposition.

EXAMPLE 4 5 parts of ethyl 6-hydroxy-2-phenylpyrimid-4-ylacetate areadded at 0 C. to a solution of 4 parts of diazomethane in 1000 parts ofether. The mixture is stirred at 0 C. for 18 hours. The excessdiazomethane is removed by distillation, and the ether is thenevaporated. The residual oil is dissolved in 10' parts of benzene andsubjected to chromatography on a column containing 150 parts ofmagnesia-silica gel. The column is eluted with 600 parts of benzene andthen with parts of 5:95 v./v. ethyl acetate2benzene. The solvent isremoved from the eluate by evaporation under reduced pressure and theresidual oil is distilled in vacuo. There is thus obtained ethyl6-methoxy-2-phenylpyrimid 4 ylacetate, B.P. 146152 C./0.5 mm., M.P.43-47 C.

1 1 EXAMPLE A mixture of parts of ethyl 2-p-chlorophenyl-4-hydroxypyrimid-S-ylacetate, 20 parts of phosphorus oxychloride and 100parts of benzene is refluxed for 1.5 hours and then cooled to ambienttemperature. An excess of 10% aqueous sodium bicarbonate is added, andthe henzene phase is separated, Washed with water, and dried withanhydrous magnesium sulphate. The solvent is evaporated and the residueis crystallised from petroleum ether (B.P. 60-80 C.). There is thusobtained ethyl 4-chloro 2 p-chlorophenylpyrimid-S-ylacetate, M.P. 94- 96C.

The ethyl 2-pchlorophenyl-4-hydroxypyrimid-5-ylacetate used as startingmaterial may be obtained as follows:

4.6 parts of sodium are dissolved in 120 parts of dry ethanol and 38parts of p-chlorobenzamidine hydrochloride are added to the solution,the temperature not being allowed to exceed 10 C. When completedissolution is obtained, 41 parts of diethyl formylsuccinate are added,the mixture is stirred at ambient temperature for 2 hours, and is thenrefluxed for 2 hours. The mixture is cooled and then filtered. The solidresidue is extracted 4 times with hot chloroform, and the solvent isevaporated from the combined extracts. The residue is crystallized fromethanol, and there is thus obtained ethyl2-p-chlorophenyl-4-hydroxypyrimid-5-ylacetate, M.P. 235 C.

EXAMPLE 6 A mixture of 5 parts of ethyl4-chloro-2-ip-chlorophenylpyrimid-S-ylacetate, 5 parts of zinc dust, 100parts of water, and 40 parts of dioxan is refluxed for 48 hours. Themixture is filtered while hot, and the solid residue is washed with 50parts of hot dioxan. Both the solid residue (A) and the combinedfiltrate and washings (B) are retained. The solid residue (A) isextracted three times with 100 parts of 5% aqueous sodium hydroxide. Thecombined extracts are acidified with acetic acid, and extracted with 5portions of 30 parts of ethyl acetate. The combined ethyl acetateextracts are washed with water, and then dried over anhydrous magnesiumsulphate. The solvent is evaporated in vacuo giving a residue (C). Thesolvent is evaporated in vacuo from the combined filtrate and washings(B), and the residue is combined with residue (C). 10 parts of 8%aqueous sodium hydroxide are added, and the mixture is refluxed for 1%hours. The solution is cooled and acidified with acetic acid, and isthen extracted with 6 portions, each of 30 parts of ethyl acetate. Thecombined extracts are washed with water, dried with anhydrous magnesiumsulphate, and filtered; the solvent is evaporated. The residue issuccessively crystallized from aqueous ethanol and ethanol, and there isthus obtained 2-p-chlorophenylpyrimid-S-ylacetic acid, M.P. 205206 C.

EXAMPLE 7 A solution of 0.23 part of sodium in 6 parts of methanol isadded to a solution of 3.1 parts ofethyl-4-chlorop-chlorophenylpyrimid-S-ylacetate in 50 parts of xylene.The mixture is refluxed for 16 hours and the solvent is then evaporatedin vacuo. The residue is refluxed for 2 hours with 50 parts of 5%aqueous sodium hydroxide, and the solution is then cooled. The solutionis acidified with acetic acid, and extracted 4 times with ethyl acetate.The combined ethyl acetate extracts are washed with water and then driedwith anhydrous magnesium sulphate. The solvent is evaporated and theresidue is crystallised from methanol. There is thus obtained2-p-chlorophenyl-4- methoxypyrimid-5-ylacetic acid, M.P. 176-177 C.

EXAMPLE 8 In a similar manner to that described in Example 1,

using the papropriate hydroxypyrimidine derivative as starting material,the following compounds are obtained:

CHrCO O C2H5 Initial purification is accomplished by chromatography on acolumn containing magnesia-silica gel. The column is eluted withchloroform.

The ethyl 2-p-chlorophenyl-6-hydroxypyrimid-4-ylacetate used as startingmaterial above may be obtained as described in Example 1. Alternativelyand preferably it can be obtained as follows: V

12.64 parts of sodium are dissolved in 50 parts of dry ethanol. parts ofp-chlorobenzamidine hydrochloride are dissolved in 400 parts of dryethanol, and added to the sodium ethoxide solution. 111.1 parts ofdiethyl acetonedicarboxylate are added and the mixture is heated underreflux for 6 hours. After cooling the solid material is collected byfiltration, stirred for 30 minutes with 100 parts of water and againcollected by filtration. After drying, the solid material is shaken with600 parts of chloroform until no more solid dissolves. The chloroformsolution is filtered and evaporated to dryness in vacuo. There is thusobtained ethyl Z-p-chlorophenyl-6-hydroxypyrimid-4-ylacetate, M.P.169-170 C.

In a similar manner, using the appropriate amidine as starting material,the following compounds are obtained:

N CHzC O O C 2H6 Recrystallisation Melting Y solvent point C 4-bromophenyl Ethanol l 175-177 3,4-dichlorophenyl Ethyl acetate 178-182 1The treatment with chloroform is omitted in this case.

EXAMPLE 9 Dry hydrogen is bubbled for 5 minutes through a mixture ofparts of dry benzene, 3.19 parts of phosphorus oxybromide and 1.1 partsof N,N-diethylaniline. 2.2 parts of ethyl2-p-chlorophenyl-6-hydroxypyrirnid-4-ylacetate are added and the mixtureis refluxed under nitrogen for 3 hours, and then allowed to stand atambient temperature for one day, The benzene is removed by evaporationunder reduced pressure. The solid residue is stirred with 100 parts ofice and the aqueous suspension is extracted 3 times with 50 parts ofether. The ethereal extracts are combined, washed successively with 10parts of water, 10 parts of saturated sodium bicarbonate solution and 10parts of water, dried with anhydrous magnesium sulphate, and evaporatedto dryness in vacuo. The residue is crystallised from ethanol. There isthus obtained ethyl 6-bromo- 2-p-chlorophenylpyrimid-4-ylacetate, M.P.89-90 C.

13 EXAMPLE 10 omooon N Position crystallisation of acetic solvent midsubfor stituent ester Petroleum ether (60-80 C). 5 Petroleum ether R isCH3 4-brornophenyl 4 Phenyl 4-chlorobenzyl 1 In these cases the methanolis evaporated before the addition of water. In each case theacidification oi the filtrate is efiected with glacial acetic acid(instead of 2N-hydrochlor1c acid).

2 Softens at 65.5 M.P. 129-130.

EXAMPLE 11 11.18 parts of sodium are added to 1000 parts of drymethanol. 75.6 parts of ethyl6-chloro-2-p-chlorophenylpyrimid-4-ylacetate are added, and the solutionis stirred for 18 hours at ambient temperature. The solution isevaporated to a small volume under reduced pressure and the resultingmixture is filtered. The solid residue is shaken with 600 parts ofchloroform, the insoluble material is removed by filtration (and dealtwith further as described below) and the chloroform removed from thefiltrate by evaporation under reduced pressure. The residual solid iscrystallised from methanol and there is thus obtained methyl2-p-chlorophenyl-6-methoxypyrimid-4- ylacetate, M.P. 78-80 C.

The material which is insoluble in chloroform is shaken with a mixtureof 20 parts of water and 20 parts of chloroform. The two phases areseparated and the aqueous phase is acidified with glacial acetic acid.The resulting mixture is filtered and the solid residue is dried. Thereis thus obtained 2-p-chlorophenyl-6-methoxypyrimid-4-ylacetic acid, M.P.123 C.

In a similar manner using the appropriate 6-chloro compound as startingmaterial, the following compounds can be obtained:

Position crystallisation of acetic solvent acid subfor M.P. C. M.P., C.,Y stituent ester R is CH; R is H 3-ehlorophenyl 4 88-91 3,4-dichloro- 4Petroleum ether 66-68 phenyl. (40-60 "C 1 Elthyl 6 chloro 2 mchlorophenyl-py-rirnid 4 ylace tate (M.P. 80-82 C.) which is used asstarting m'aterlal 15 obtained by a similar method to that described inExample 8 from ethyl 2 m chlonophenyl 6 hydroxypyrimid 4 y1- acetate(M.P. 236-238 0.), and the latter compound is likewise 8obtained by asimilar method to that described in E xample.

EXAMPLE 13 0.74 part of sodium is dissolved in 25 parts of dry ethanol,and a slurry of parts of ethyl6-chloro-2-pchlorophenylpyramid-4-ylacetate and 60 parts of dry ethanolis added dropwise at a temperature below 15 C. The mixture is stirredfor 3 hours at ambient temperature, and then kept for 48 hours atambient temperature. The resulting mixture is filtered and 1 part ofWater is added to the filtrate. The resulting mixture is filtered andthe crystalline solid residue and filtrate are retained. The filtrate isevaporated to dryness under reduced pressure, and the residue iscrystallized from a mixture of ethanol and ether. The two crystallinesolids are combined, triturated with 50 parts of ether and collected byfiltration. There is thus obtained sodium2-p-chlorophenyl-6-ethoxypyrimid-4-ylacetate monohydrate, M.P. 236 C.(with decomposition).

EXAMPLE 14 0.39 part of sodium is dissolved in 250' parts of liquidammonia in the presence of a trace of ferric nitrate. When the formationof sodamide is complete, as shown by a colour change from dark blue togrey, a solution of 5 parts of methyl 2-p-chlorophenyl-6-methoxypyrimid-4- ylacetate in 50 parts of dry ether is added. The mixture isrefluxed for 45 minutes, and a solution of 2.44 parts of methyl iodidein 10 parts of dry ether is added. The mixture is stirred at -70 C. for24 hours. 1.2 parts of ammonium chloride are added and the ammonia isallowed to evaporate. The residue is shaken with a mixture of equalparts of water and ether. After separation of the phases, the aqueousphase is extracted with ether. The combined ethereal solutions arewashed with water until the washings are neutral, dried over anhydrousmagnesium sulphate, filtered, and evaporated to dryness in vacuo. Theresidual oil is kept at ambient temperature for 3 days. The resultingmixture of crystalline solid and oil is filtered and both the oily solidresidue and filtrate A (see Example 15) are retained. The oily solidresidue is presesd between two porcelain tiles, to remove the oil. Theresulting solid is triturated with petroleum ether, b.p. 40-60" C. Thereis thus obtained methyl a-[2-p-chlorophenyl-fi-methoxypyrimid-4-yl1propionate, M.P. 56.5 60 C.

EXAMPLE 15 0.157 part of sodium is dissolved in 50 parts of liquidammonia in the presence of a trace of ferric nitrate. When the formationof sodamide is complete, a solution of 1 part of filtrateA (see Example14) in 20 parts of ether is added, and the mixture is stirred for 1hour. A solution of 0.971 part of methyl iodide in 10 parts of dry otheris added, and the mixture is stirred at 33 C. for 24 hours. 0.37 part ofammonium chloride is added and the ammonia is allowed to evaporate. Theresidue is shaken with a mixture of equal parts of water and ether, andafter separation of the phases the aqueous phase is extracted twice withether. The combined ethereal solutions are dried over anhydrousmagnesium sulphate, filtered and evaporated to dryness under reducedpressure. The residual oil is purified by preparative thin layerchromatography on silica plates with a fluorescent indicator. The platesare developed in acetone/petrol 1:3. The area of silica containing theproduct is removed from the plate and extracted with chloroform. Thechloroform solution is filtered and evaporated to dryness under reducedpressure. There is thus obtained methyl a[2-p-chlorophenyl-6-methoxypyrimid-4-yl]isobutyrate, M.P. 74.579.5 C.

EXAMPLE 16 5 parts of methyl 2-p-chlorophenyl-6-methoxy pyrimid-4-ylacetate are dissolved in 200 parts of dry methanol. 2.56 parts ofhydrazine hydrate are added, and the mixture is heated under reflux for4 hours. After cooling, the methanol is removed by evaporation underreduced pressure. The solid residue is crystallised from ethanol andthere is thus obtained2-p-chlorophenyl-6-methoxypyrimid-4-ylacethydrazide, M.P. 154-155 C.

1 5 EXAMPLE 17 0.55 partfof glycirie ethyl ester hydrochloride aresuspended in 5 parts of dry chloroformfand 0.4 part of triethylamine isadded. After stirring for 15 minutes, the resulting solution is cooledin an ice bath and 1 partof 2-p-chlorophenyl-6-methoxypyrimidl-ylaceticacid is added. 0.8 part of dicyclohexylcarbodiimide is added, themixture is stirred at C. for 2 /2 hours, then at ambient temperature for2 days, and then filtered. The filtrate is washed twice, with 15 partsof saturated sodium bicarbonate solution. The organic solution is; driedover anhydrous magnesium sulphate, filtered, and evaporated to drynessunder reduced pressure. The residue is crystallised from ethanol Thereis thus obtained ethyl amp-chlorophenyl- -metlioxypyrimid-4-ylacetamido]acetate, M.P.I 119- 121 C. n I j T EXAMPLE 18EXAMPLE 19 To 0.5 part of"2-p-chlorophenyl-6-methoxypyrimid-4- ylaceticacid is added a solution 05 0.04 part of sodium in 8 parts of dryethanolJThe mixture is stirred at ambient temperature for 2 hours andthe ethanol is 'then removed by evaporation under reduced pressure. 0.27part of diethylaminoe'thyl chloride dissolved in 10 parts of dry acetoneis added to the residue and the mixture is heated under reflux for 'l8hours, and then evaporated to dryness under reduced pressure. To theresidue are added 10 parts of water, and the suspension is extracted 3times with 5 parts of ether. The combined ethereal solution is washedwith water, dried over anhydrous magnesium sulphate, filtered andevaporated to dryness under reduced pressure. The residual oil isstirred with 10 parts of 2 N- hydrochloric acid for minutes and thesolution is extracted 3 times with 5 parts of ether. The aqueous acidphase is basified with 2 N-sodium hydroxide and extracted 3 times with10 parts of ether. The combined ethereal solution is washed twice with'5parts of water, dried over anhydrous magnesium sulphate, filtered, andevaporated under reduced pressure. The residual oil is dissolved inethyl acetate and a saturated solution of oxalic acid in dry ether isadded. Dry ether is added to precipitate the oxalate as an oil. Thesolvents are decanted away from the oil, which is repeatedly dissolvedin dry ethanol and reprecipitated with dry ether, until a solid isobtained. The solid is crystallised from a mixture of ethanol and ether.There is thus obtained fi-diethylaminoethyl2-p-chlorophenyl-6-methoxypyrimid-4-ylacetate acid oxalate, M.P. 120-122EXAMPLE A mixture of 100 parts of dry toluene, 0.371 part of aluminiumfoil, 0.02 part of carbon tetrachloride,'0.0028 part of mercuricchloride, and i332 parts of dry benzylalcohol, is heated under refluxfor 2 hours, by which time all the aluminium has dissolved. 3 parts ofmethyl 2-pchlorophenyl-6-methoxypyrimid-4-ylacetate are added, andheating is continued for 4 hours. The solution is evaporated underreduced pressure at 60 C. The residual oil is mixed with 15 parts ofwater and extracted 3 times with 100 parts of ether. The combinedethereal solution is dried with anhydrous magnesium sulphate, filtered,and evaporated to dryness. The excess benzyl aleohol is 'removed bydistillation at 0.2mm. pressure and 60 C. The residual oily solid iscrystallised from petroleum ether 16 (B.P. -100" 0. and then frompetroleum ether (B.P. 6080 There is thus obtained benzyl2-p-chlorophenyl-G-mthoxypyrimid-4-ylacetate, M.P. 92 C.

EXAMPLE 21 3 parts of methyl 2-p-chlorophenyl-6-methoxypyrimid-4-ylacetate are mixed with 10.2 parts of freshly distilled aluminiumisopropoxide and 20 parts of dry toluene, and the mixture is refluxedfor 4 hours and then kept for 18 hours at ambient temperature. Thetoluene is e'efaporated under reduced pressure and the residue is mixedwith water, and ether. The resulting mixture is filtered, and both thesolid residue and filtrate are retained. The solid residue is washedseverel times with ether. The ethereal washings are combined with theabovemergtioned filtrate, and the ethereal phase is separated, driedover anhydrous magnesium sulphate, filtered, and evaporated underreduced pressure. The residual solid is crystallized from petroleumether (B.P. 4060 CI). There is thus obtained isop'ropyl2-p-chlorophenyl-6-methoxypyrimid-4- ylacetate, M.P. 6466 C. 1

EXAMPLE 22 1.79 parts of 2 N-sodium hydroxide solution are added to 1part of 2 p chlorophenyl 6 methoxypyrimid- 'lylacetic acid. 10 parts ofwater are added, followed by a solution of 0.5 part of calcium chloridein 5 parts of water. The resulting precipitate is collected byfiltration, washed with water and dried for 15 hours in vacuo at C.There is thus obtained calcium 2-p-chlorophnyl- 6-methoxypyrimid-4ylacetate monohydrate, M.P. 220- 245 C. e EXAMPLE 23 The processdescribed in Example 22 is repeated except that the 0.5 part of calciumchloride in 5 parts of water is replaced by 1.08 parts of aluminiumsulphate tetradecylhydrate in 20 parts of water. In a similar mannerthere is obtained aluminum2-p'=chlorophenyl-6-methoxypyrimid-4-ylacetate hem ihydrate, M.P.208-212 C.

EXAMPLE 24 0.3 part of methyl 2-p-chlorophenyl-@methoxypyrimid-4-ylacetate is dissolved in 10 parts of dry ether. A saturated solutionof hydrogen chloride in dry ether is added until precipitation iscomplete. The precipitate is collected by filtration, washed; with dryether and crystallised from dry ethanol. There is thus obtained methyl2-p-chlorophenyl-6methoxypyrimid-4-ylacetate hydrochloride, M.P. 89.592C, e e

- i 7 EXAMPLE 25 1 part of methyl2-p-chlorophenyl-6-methoxypyrimidi-ylacetate and 0.536 part offreshly-fused sodium acetate are dissolved in 5 parts of stirred glacialacetic acid. 5.22 parts of bromine dissolvedain 5 parts of glacialacetic acid are slowly added. The mixture is stirred for 1 hour atambient temperature and then poured into 50 parts of water. 2N-ammoniurn hydroxide solution is added until the mixture has pH 4,andethe mixture is then extracted 3 times with 50 parts of ether. Thecombined ethereal extracts are washed twice with @10 parts of water,dried over anhydrous magnesium sulphate, filtered and evaporated todryness. The residue is crystallised from petroleum ether (B.P. 6080C.). There is thus obtained methyl 2 p chlorophenyl 6 methoxypyrimid 4yl 0a,- dibromoacetate, M.P. 139.5l42 C.

EXAMPLE 26 The process described in Example 25 is repeated except that0.522 part of bromine is used in place of the 5.22 parts of bromine Theresidue after evaporation of the ethereal extracts is purified bychromatography on a column containing magnesia-silica gel. The column iseluted with s'olvents increasing in polarity from petroleum ether (B.P.60-80 C.) to a mixture of ethyl acetate-benzene (10:90 v./v.). Theeluates are evaporated to dryness under re- 1 7 duced pressure. There isthus obtained methyl 2-p-chlorophenyl-6-methoxypyrimid-4-yl-ot-bromoacetate, M.P. 84- 88 C., and methyl 2-p-chlorophenyl-6-methoxypyrimid-4-yl-a,a-dibromoacetate, M.P. 139.5-142 C.

EXAMPLE 27 3 parts of 2-p-chlorophenyl-4-cyanomethylpyrimidine arewarmed at 100 C. for 5 minutes together with 10 parts of 96% sulphuricacid. After cooling, the solution is poured into 100 parts of crushedice, and the mixture is stirred, and neutralised at l C. withconcentrated ammonium hydroxide solution. The resulting precipitate iscollected by filtration, dried, and crystallised from ethanol. There isthus obtained 2-p-chlorophenylpyrimid-4-ylacetamide, M.P. 158-16l C.

EXAMPLE 28 3 parts of 2-p-chlorophenyl-4-cyanomethylpyrimidine aredissolved in a mixture of 8 parts of dry methanol and 30 parts of drybenzene. The solution is saturated at 0 C. with dry hydrogen chloridegas, and the mixture is kept at C. for 3 days. The solvent is thenremoved by evaporation under reduced pressure, and 100 parts of waterand 50 parts of benzene are added to the residue. After stirring for 1hour, the mixture is separated and the aqueous phase is extracted with50 parts of benzene. The combined benzene solutions are dried overanhydrous magnesium sulphate, filtered and and evaporated to drynessunder reduced pressure. The solid residue is crystallised from petroleumether (B.P. 60-80 C.) and then r from methanol. There is thus obtainedmethyl 2-p-chlorophenylpyn'mid-4-ylacetate, M.P. 82-83.5 C.

The 2-p-chlor0phenyl-4-cyanomethylpyrimidine used as starting materialin this example and in Example 27 may be obtained as follows:

9 parts of B-(2-p-chlorophenylpyrimid-4-yl)-a-oximinopropionic acid isheated at 100 C. with 30 parts of acetic anhydride. When gas evolutionstops, the solution is cooled, poured into 150 parts of water, andwarmed to 60 C. to destroy the excess of acetic anhydride. Thecrystalline precipitate is collected by filtration, dried, andcrystallised from methanol. There is thus obtained2-pch10rophenyl-4-cyanomethylpyrimidine, M.P. 124l27 C.

The B-(2-p-chlorophenylpyrimid-4-yl)-a-oximino propionic acid used asstarting material may be obtained as follows:

12 parts of ethyl B-(2-p-chlorophenylpyrimid-4-yl)-aoximinopropionateare heated under reflux for 30 minutes with 150 parts of 2 N-sodiumhydroxide solution and 50 parts of methanol. The solution is cooled, themethanol is removed by evaporation under reduced pressure, and theresidue is acidified with 2 N-hydrochloric acid. The crystallineprecipitate is collected by filtration, dried, and crystallised frommethanol. There is thus obtainedB-(2-pchlorophenylpyrimid-4-yl)-u-oximinopropionic acid, M.P. 194-195 C.

The ethyl B-(2-p-chlorophenylpyrimid-4-yl)-a-oximinopropionate used asstarting material may be obtained as follows:

50 parts of ethyl 2-p-chloropyrimid-4-yl-pyruvate are added to a mixtureof 13.5 parts of fused sodium acetate and 11.4 parts of hydroxylaminehydrochloride in 30 parts of water and 400 ml. of ethanol. The mixtureis heated under reflux for 2 /2 hours. Water is added carefully and,after cooling, the crystalline product is collected by filtration. Thereis thus obtained ethyl,B-(Z-p-chlorophenylpyrimid-4-yl)-a-oximinopropionate hemihydrate. Thiscompound begins to melt at 64 C., and there is a tendency for it toresolidify at 80 C. If the sample is cooled until it is completely solidand then reheated, the melting point is 122-124 C.

The ethyl 2-p-chlorophenylpyrimid-4-ylpyruvate used as starting materialmay be obtained as follows:

12 parts of potassium are added to a mixture of 60 parts of dry ethanoland 750 parts of dry ether. When the potassium has dissolved, 40.65parts of diethyl oxalate are added over a period of 10 minutes, followedby 62 parts of 2 p chlorophenyl 4 methylpyrimidine in 400 parts ofether. The mixture is kept at ambient temperature for 8 days andoccasionally stirred. The precipitated solid is collected by filtrationand washed witlh 200 parts of dry ether. The solid is dissolved in 600parts of water, and the solution is washed with 200 parts of ether, andflhen acidified with glacial acetic acid. The resulting precipitate iscollected by filtration and crystallised from ethanol. There is thusobtained ethyl 2 p chlorophenylpyrimid-4-ylpyruvate, M.P. 147-148" C.

2 p chlorophenyl 4 methylpyrimidine may be obtained as follows:

19.1 parts of p-chlorobenzamidine hydrochloride are dissolved in 75parts of ethanol, and the solution is added to a solution of 2.5 partsof sodium in 75 parts of ethanol. The precipitated sodium chloride isremoved by filtration and the filtrate is mixed with 13.2 parts offormyl acetone dimethyl acetal. After heating under reflux for 4 hours,the solution is cooled in ice and neutralised with acetic acid. Thecrystalline precipitate is collected by filtration and retained. Thefiltrate is evaporated to dryness under reduced pressure, and the solidresidue is dissolved in ether. The ethereal solution is washed 3 timeswith l N- sodium hydroxide, dried over anhydrous magnesium sulphate,filtered, and evaporated to dryness under reduced pressure. The residueis crystallised from ethanol, and combined With the crystallineprecipitate obtained above. The combined solids are crystallised fromethanol, and there is obtained 2 p chlorophenyl 4 methylpyrimidine, M.P.87-90 C.

EXAMPLE 29 3 parts of a 50% dispersion of sodium hydride in oil arewashed free of oil with petroleum ether (B.P. 60- C.) and added to 15parts of diethyl carbonate. When the evolution of gas has ceased, 2parts of 6-p-chlorophenyl 2 ethoxy 4 methylpyrimidine are added and themixture is refluxed in an atmosphere of nitrogen for 90 minutes. Themixture is cooled and 30 parts of benzene are added. The mixture isfiltered and the solid residue is washed well with dry benzene. Thesolid is then added carefully to 50 parts of ice water. The insolublematerial is filtered off, and dissolved in 20 parts of 1 N-sodiumhydroxide solution at 50 C. for 15 minutes. The solution is treated withdecolourising carbon, filtered, and cooled. The resulting crystallinesolid is collected by filtration, Washed with a small amount of water,then with acetone, and dried. There is thus obtained sodium 6 pchlorophenyl 2 ethoxy pyrimid 4 ylacetate hemihydrate, M.P. 178-182 C.

The 6 p chlorophenyl 2 ethoxy 4 methylpyrimidine used as startingmaterial may be obtained as follows:

3.6 parts of 2 chloro 6 p chlorophenyl 4 methylpyrimidine are heatedunder reflux for 1 hour with a solution of 0.7 part of sodium in 50parts of dry ethanol. After cooling, the ethanol is removed byevaporation under reduced pressure. 20 parts of water are added to theresidue, and the solid material is extracted into 50 parts of ether. Theaqueous phase is extracted twice with 50 parts of ether, and thecombined ethereal solution Washed with 20 parts of water, dried overanhydrous magnesium sulphate, filtered, and evaporated to dryness underreduced pressure. There is thus obtained 6-p-chlorophenyl-2-ethoxy-4-methylpyrimidine, M.P. 68-69 C.

The 2 chloro 6 p chlorophenyl 4 methylpyrimidine used as startingmaterial may be obtained as follows:

14.7 parts of 6 p chlorophenyl 2 hydroxy 4- methylpyrimidine are mixedwith 60 parts of phosphorus oxychloride and 10 parts ofN,N-diethylaniline and heated under reflux for 2 /2 hours. Aftercooling, the excess phosphorus oxychloride is removed by evaporationunder reduced pressure, and the residue is poured into 500 parts of icewater. The resulting precipitate is extracted into 19 benzene, thebenzene extract is washed with 50 parts of Water, dried over anhydrousmagnesium sulphate, filtered, and evaporated to dryness under reducedpressure. The solid residue is crystallised from petroleum ether, (B.P.6080 C.). There is thus obtained2-chloro-6-p-chlorophenyl-4-methylpyrimidine, M.P. 115-117 C.

The 6 p chlorophenyl 2 hydroxy 4 methylpyrimidine used as startingmaterial may be obtained as follows:

15.2 parts of 2 amino 6 p chlorophenyl 4 methylpyrimidine are heatedunder reflux for 18 hours with 150 parts of concentrated hydrochloricacid. After cooling, the solution is diluted with water, and the pHadjusted to 7 by the addition of concentrated sodium hydroxide solution.The resulting precipitate is collected by filtration, washed with water,and dried. There is thus obtained 6 p chlorophenyl 2 hydroxy 4methylpyrimidine, M.P. 274-280 C.

The 2-amino-6-p-chlorophenyl-4-methylpyrimidine used as startingmaterial may be obtained as follows:

18 parts of guanidine carbonate are intimately mixed with 21.6 parts ofp-chlorobenzoyl acetone, and the mixture is heated at 140 C., for 1hour. After 30 minutes the reaction mixture solidifies. After coolingthe solid is shaken for minutes with 100 parts of water, and the mixtureis filtered. The solid residue is heated under reflux for minutes with300 parts of ethanol, and then cooled. The crystalline precipitate iscollected by filtration and dried. There is thus obtainedZ-amino-6-p-chlorophenyl-4- methylpyrimidine, M.P. 199202 C.

EXAMPLE 30 4 parts of sodium 6-p-chlorophenyl-2-ethoxypyrimid-4-ylacetate are dissolved in 100 parts of water, and the solution isacidified with glacial acetic acid. The precipitate is collected byfiltration, washed with water, and dried. There is thus obtained6-p-chlorophenyl-2-ethoxypyrimid-4-ylacetic acid, M.P. 8586 C.

EXAMPLE 3 1 The procedure described in Example 27 is repeated exceptthat 4-p-chlorophenyl-2-cyanomethylpyrimidine is used in place of2-p-chlorophenyl-4-cyanomethylpyrimidine. There is thus obtained4-p-chlorophenylpyrimid-2- yl-acetamide, M.P. 164165.5 C.

By repeating the procedures described in Example 28 and using theappropriate starting materials, the following intermediates (requiredfor the preparation of 4-p-chlorophenylpyrimid-Z-ylacetamide) areobtained: 4 p-chlorophenyl 2 cyanomethylpyrimidine, M.P. ll3-ll5 C.,8-(4 p chlorophenylpyrimid 2 yl) a oximino propionic acid, M.P. 174176C., and ethyl [3-(4-p-ehlorophenylpyrimid -2 yl) 0c oximinopropionate,M.P. 166170.5 C.

The ethyl 4 p chlorophenylpyrirnid 2 ylpyruvate used as startingmaterial in the preparation of the lastnamed compound may be obtained asfollows:

20.4 parts of 4-p-chlorophenyl-Z-methylpyrimidine are dissolved in 200parts of dry dimethylformamide. 36.5 parts of diethyloxalate are added,followed by 7.2 parts of a 50% dispersion of sodium hydride in oil. Themixture is heated to 65 C., whereupon a vigorous exothermic reactionbegins. When the reaction is complete, the mixture is cooled, pouredinto 1000 parts of water, and acidified with glacial acetic acid. Thesuspension is stirred for one hour, and the precipitate is thencollected by filtration, dried and crystallised from ethyl acetate.There is thus obtained ethyl 4 p-chlorophenylpyrirnid-2-yl-pyruvate,M.P. 153-155" C.

The 4 p-chlorophenyl 2 methylpyrimidine used as starting material may beobtained as follows:

29 parts of sodium are dissolved in 600 parts of dry ethanol. Thesolution is cooled and 119 parts of acetamidine hydrochloride are added.After stirring for 30 minutes, the precipitated sodium chloride isremoved by filtration and the filtrate is cooled to 10 C. 63.3 parts ofp-chlorophenyl ,B-chlorovinyl ketone dissolved in 150 parts of dryethanol are added at such a rate that the temperature does not exceed 10C. The mixture is stirred at ambient temperature for 30 minutes. Thesolution is then evaporated to dryness under reduced pressure, and theresidue is crystallised from ethanol (with cooling at -40 C.). Thecrystalline solid is collected by filtration, and dried. The filtrate isevaporated to dryness, and the residue is dissolved in 500 parts of 2N-hydrochloric acid. The solution is washed 3 times with 100 parts ofether, treated with decolourising carbon, filtered, and adjusted to pH 6with sodium hydroxide solution. The resulting mixture is filtered,combined with the above-mentioned, crystalline solid. The solid isdissolved as far as possible in petroleum ether (B.P. 60-80" C.), underreflux, the mixture is filtered while hot, and the filtrate is allowedto cool to ambient temperature. The resulting mixture is filtered. Thereis thus obtained, as solid residue, 4-p-chlorophenyl-2-methylpyrimidine, M.P. 92.5-94.5 C.

EXAMPLE 32 2.9 parts of 2-p-chlorobenzyl-6-methoxypyrimid-5-ylaceticacid and 1.16 parts of N,N-diethylethylenediamine are dissolved in 30parts of dry chloroform, and the solution is stirred and cooled to 0 C.2.23 parts of dicyclohexylcarbodiimide are added, and the mixture iskept at ambient temperature for 4 days. The resulting precipitate isremoved by filtration, and the filtrate is evaporated to dryness. Theresidual oil is dissolved in 4 parts of ethyl acetate, and the solutionis cooled in ice for 30 minutes and the resulting mixture filtered. Thefiltrate is evaporated to dryness, and the residue is dissolved in 20parts of ether. The ethereal solution extracted 4 times with 10 parts ofwater, and then 3 times with 15 parts of 2 N- acetic acid. The aqueousacid layer is made alkaline, and extracted 3 times with 20 parts ofether. The ethereal extract is dried over anhydrous magnesium sulphate,filtered, and evaporated to dryness in vacuo. The solid residue iscrystallised from petroleum ether (B.P. 6080 C.). There is thus obtainedN-[i-diethylaminoethyl-(2-p-chlorobenzyl 6 methoxypyrimid 5yl)acetamide, M.P. 107- 109 C.

EXAMPLE 33 13.75 parts of carboxamidoacetamidine hydrochloride are addedto a solution of 2.5 parts of sodium in 300 parts of dry ethanol. Whenprecipitation is complete, the precipitated sodium chloride is removedby filtration, and the filtrate is mixed with 20.75 parts ofcup-chlorophenyl- B-dimethylaminoacrolein. The mixture is heated underreflux for 4 hours, and then kept at ambient temperature for 18 hours.The mixture is filtered and the solid residue is crystallised from amixture of ethanol and dimethylformamide. There is thus obtained5-p-chlorophenylpyrimid-2-ylacetamide, M.P. 230-239 C. (change ofcrystalline form commencing at 210 C.).

The u-p-chlorophenyl-B-dimethylaminoacrolein used as starting materialmay be obtained as follows:

230 parts of redistilled phosphorus oxychloride are slowly added to182.5 parts of stirred dry dimethyl formamide at 0 C. 85.25 parts ofp-chlorophenylacetic acid are added to the mixture, and the resultingsolution is stirred at 70 C. for 6 hours. After cooling, the mixture ispoured into 400 parts of ice and neutralised with concentrated sodiumhydroxide solution. 800 parts of potassium carbonate and 250 parts ofbenzene are added, and the mixture is stirred and heated under reflux atC. for 1 hour; the mixture is cooled and separated. The aqueous phase isextracted 4 times with 250 parts of benzene. The combined benzeneextracts are washed with 250 parts of water, dried over anhydrousmagnesium sulphate, filteredand evaporated to dryness in vacuo. Thesolid residue, is crystallised from benzene. There is thus obtainedu-p-chlorophenyl-;3-dimethylaminoacrolein, M.P. 119-120 C.

21 EXAMPLE 34 parts of S-p-chlorophenylpyrimid 2 ylacetamide are stirredWith 500 parts of dry ethanol. Dry hydrogen chloride gas is passedthrough the mixture for 4 hours while heating under reflux. Aftercooling, the ethanol is evaporated in vacuo. parts of water are added,the suspension is shaken With parts of saturated sodium bicarbonatesolution, and the resulting solid material is extracted into 100 partsof ether. The ethereal solution is dried with anhydrous magnesiumsulphate, filtered, and evaporated to dryness in vacuo. The solidresidue is crystallised from ethanol. There is thus obtained ethyl5-pchlorophenylpyrimid-Z-ylacetate, M.P. 7475.5 C.

EXAMPLE The process described in Example 33 is repeated except thata-carboxamidopropionamidine hydrochloride is used in place ofcarboxamidoacetamidine hydrochloride. There is thus obtaineda-[5-p-chlorophenylpyrimid-2-yl]propionamide, M.P. 228229 C.(crystallised from methanol).

EXAMPLE 36 The process described in Example 34 is repeated except thata- [-p-chlorophenylpyrimid-Z-yl]propionamide is used in place ofS-p-chlorophenylpyrimid-Z-yl-acetamide, and methanol is used instead ofethanol. The product is purified by preparative thin layerchromatography on silica plates with a fluorescent indicator. Elution ofthe plates is carried out with acetone/ petroleum ether (B.P. 80100 C.)1:3. The required bands are scraped from the plates. and material isrecovered by extraction of the silica with acetone. After filtration,the acetone is evaporated in vacuo and the residue is crystallised fromaqueous methanol. There is thus obtained methyl a-[5-p-chlorophenylpyrimid-2-yl-1propionate, M.P. 73-76 C.

EXAMPLE 37 Ethyl 6 chloro-2-p-trifluoromethylphenylpyrimid-4-yl acetate(M.P. -47 C.), is obtained from the corresponding 6-hydroxy compound.(M.P. 200201), in analogous manner to that described in Example 1.

The 6-hydroxy compound used as starting material may be obtained fromp-trifluoromethylbenzamidine hydrochloride in analogous manner to thatdescribed in Example 1.

p-Trifluoromethylbenzamidine hydrochloride itself is obtained asfollows:

12.2 parts of p-trifluoromethylbenzonitrile are dissolved in a mixtureof 9 parts of dry ethanol and 20 parts of dry benzene. 8 parts of dryhydrogen chloride are passed into this solu ion below 5 C., and theresulting mixture is kept at 0 C. for 3 days and then evaporated todryness in vacuo. The residue is dissolved in 200 parts of ethanolsaturated with dry ammonia, and the mixture is stirred for 3 days at 37C. The mixture is evaporated to dryness in vacuo, and the residual gumis washed with dry ethyl acetate and filtered. The residue is dried andcrystallised from Water. There is thus obtainedp-trifluoromethylbenzamidine hydrochloride, M.P. 165l69 C.

EXAMPLE 3 8 7.6 parts of ethyl6-chloro-2-p-trifluoromethylphenylpyrimid-4-ylacetate are added to asolution of 1 part of sodium in 100 parts of methanol. The mixture isrefluxed for 2 hours and then evaporated to dryness. The residue isextracted with 250 parts of cold chloroform, and the resulting mixtureis filtered. The solid residue is Washed Well with petroleum ether (B.P.6080 C.), and then dissolved as far as possible in 400 parts of ice coldwater, and the mixture is filtered. The filtrate is acidified at 0 C.with acetic acid, and the resulting solid is collected by filtration,washed With water and dried in vacuo. There is thus obtained 6methoxy-2-p-trifluoromethylpyrimid-4- ylacetic acid, M.P. -52 C. withdecomposition.

22 EXAMPLE 39 18.4 parts of ethyl 2-p-chlorophenyl-6-hydroxy-4-methylpyrimid-S-ylacetate, 30 parts of phosphoryl choride, and 150 partsof benzene are refluxed for 3 hours. The mixture is cooled and pouredonto 250 parts of ice and water. This mixture is stirred, and sodiumbicarbonate is added until the aqueous layer is no longer acid. Thebenzene layer is separated, washed with water, dried over anhydrousmagnesium sulphate and evaporated to dryness. The residual solid iscrystallised from ethanol, and there is obtained ethyl6-chloro-2-p-chlorophenyl-4-methylpyrimid-S-ylacetate, M.P. 105106 C.

Ethyl 2 p chlorophenyl-6-hydroxy-4-methylpyrimid- S-ylacetate may beobtained as follows:

4.4 parts of sodium are dissolved in 250 parts of ethanol, and 36 partsof p-chlorobenzamidine hydrochloride and 41 parts ofdiethylacetylsuccinate are added. Th mixture is stirred at roomtemperature for 2 hours, and then boiled under reflux for 2 hours. Theresulting mixture is extracted with 1300 parts of chloroform, and thechloroform extract is filtered. The filtrate is evaporated to dryness,and the solid residue is crystallised from ethanol. There is thusobtained ethyl 2-p-chlorophenyl- 6-hydroxy-4-methylpyrimid-S-ylacetate,M.P. 236237 C.

EXAMPLE 40 5 parts of ethyl6-chloro-2-p-chlorophenyl-4-methylpyrimid-5-ylacetate, 5 parts of zincdust, and 3 parts of ammonium chloride are refluxed for 24 hours in amixture of 40 parts of dioxan and 100 parts of Water. 25 parts of 40%aqueous sodium hydroxide are then added and the mixture boiled forminutes and then filtered. The cooled filtrate is acidified to pH 5 withglacial acetic acid, and then extracted with 4 portions of 50 parts ofethyl acetate. The combined ethyl acetate extracts are extracted with 4portions of 50 parts of 5% aqueous ammonium hydroxide. The combinedaqueous extract are washed with 120 parts of petroleum ether (B.P. C.).The aqueous solution is acidified While hot to pH 5 with acetic acid,and the mixture is then cooled to ambient temperature. The resultingmixture is filtered, and the solid residue is crystallised twice from amixture of benzene and petroleum ether (B.P. 60-80 C.) there is obtained2 p chlorophenyl-4-methylpyrimid-S-ylacetic acid, M.P. 167 C.

EXAMPLE 41 1 part of sodium is dissolved in 50 parts of methanol and 7parts of ethyl 6-chlor0-2-p-chlorophenyl-4-methylpyrimid-S-ylacetate areadded. The mixture is refluxed for 16 hours. The mixture is evaporatedto dryness, and 60 parts of water and 10 parts of 40% aqueous sodiumhydroxide are added to the residue. The resulting mixture is refluxedfor 1 hour. The solution is acidified with acetic acid, and extracted 4times with ethyl acetate (50 parts each time). The combined ethylacetate extracts are Washed with water and then dried over anhydrousmagnesium sulphate. The solvent is evaporated and the residue iscrystallised from a 1:1 mixture of benzene and petroleum ther (B.P. 60-80 C.). There is thus obtained 2p-chlorophenyl-6-methoxy-4-methylpyrimid-5-ylacetic acid, M.P. 193-194C.

EXAMPLE 42 Ethyl 4 chloro 2 p-fluorophenylpyrimid-5-ylacetate (M.P. 9697C.) is obtained from the corresponding 4-hydroxy compound by a similarprocess to that described in Example 5.

EXAMPLE 43 2 p fluorophenyl-4-methoxypyrimid-S-ylacetatic acid (M.P. 184C.) is obtained from ethyl 4-chloro-2-p-fluorophenylpyrimid-S-ylacetate(see Example 42) by a similar process to that described in Example 7.

2.? EXAMPLE 44 A mixture of 3.7.5 parts of sodium hydride and 35 partsof diethyl carbonate is stirred under a nitrogen atmosphere and heatedunder reflux for five minutes. 7.39 partsof4,6-dimethyl-2phenylpyrimidine are added and the mixture is stirred; andrefluxed under nitrogen for two hours. The cooled mixture is stirredwith 200 parts of benzene, filtered, and the solid residue is washedwith 50 parts of dry benzene. The combined filtrate and washiug iswashed with 100 parts of saturated sodium bicarbonate solution and thenevaporated to remove benzene and excessdiethyl carbonate. The residue iscrystallised three times from petroleum ether (BiP. 60-80 C.).

There is thus obtained diethyl 2-(4-methyl-2-phenyl- A mixture of 1 partof diethyl 2-(4-rnethyl-2-phenylpyri-mid-6-yl) malonate, 0.4 part ofsodium hydroxide, 1 part'of water and 10'parts of methanol is heatedunder reflux for one hour. The mixture is evaporated, and the residue isdistributed between 5 parts of water and parts of ether. The aqueousphase 'is separated from the 'mixture, and saturated with sodiumchloride. The resulting mixture is cooled in ice, filtered, and thesolid residue is washed with saturated aqueous sodium chloride. Thesolid is dissolved as far as possible in 5 parts of tamyl alcohol underreflux, filtered while hot, and the cooled filtrate is diluted withether to turbidity and the product allowed to crystallise. There is thusobtained sodium 4 methyl-Z-phenylpyrimid-6-ylacetate tetrahydrate, M .P.208-210" C. after shrinking and losing water at 68-70" C.

Metathesis of the above salt water with dicyclohexylammonium acetate andcrystallisation from water and then from ethyl acetate with additioii ofpetroleum ether (B.P. 6080 C.) yields dicyclohexylammonium 4-methyl-Z-phenylpyrimid-6-ylacetate monohydrate M.P. 126127 C.

EXAMPLE 46 The process described in Example 44 is repeated exceptthat2-p-chlorophenyl-4,G-dimethylpyrimidine is used as starting material inplace of 4,6-dimethyl-2-phenylpyrimidine. There is thus obtained diethyl2-(2 -p-chlorophenyl-4-methylpyrimid-6-yl)malonate, M.P. 88-90 C.

The 2-pchlorophenyl-4,6-dimethylpyrimidine used as starting material maybe obtained as follows? A mixture of 10 parts of p-chlorobenzamidinehydrochloride, 53 parts of acetylacetone, 7 parts of potassium carbonateand parts of water is heated at 100 C. for two hours. The aqueous phaseis decanted while still hot from the oily products and the oil is Washedtwice' by decantation with parts of hot water each time. The oil isdissolved as far as possible in 50 parts of methanol under reflux, thenthe mixture is filtered, and the filtrate is slowly diluted with 50parts of water, while allowing the product to 'crystallise. There isthus obtained 2-pchlorophenyl-4,fi-dimethylpyrimidine, M.P. 10l-l03 C.

EXAMPLE 47 The process-described in Example 44 is repeated except thatZ-p-chlorophenyl-S,6-dimethylpyrimidine is used as starting material inplace of 4,5-dimethyl-2-phenylpyrim idine. There is thus obtaineddiethyl 2- (2-p-chlorophenyl- 5-methylpyrimid-6-yl) malonate, M.P.95-96" C.

The 2-p-ohloropheny1-5,6-dimethylpyrimidine used as stafiing materialmay be obtained as follows:

A mixture of 5 parts of 4-chloro-2-pchlorophenyl-5,6- dirnethylpyrimidine, 8 parts of zinc dust, 8 parts of ammonium chloride, parts ofwater and 40 parts of dioxan is heated under reflux for 24 hours. Themixture is cooled and poured into a mixture'bf 500 parts of water and 10parts of acetic acid. The mixture is extracted with ether, and the etheris evaporated. The residue is crystallised from methanol (charcoaltreatment)? There is thus obtained 2 -pchlorophenyl-5,6-dimethylpyrirnidine, M.P. 113 C. Y r

4 chloro 2 p chlorophenyl 5,6 dimethylpyrimidine itself may be obtainedas follows:

A mixture of 2.0 parts of p-chlorobenzamidine hydrochloride,"8 parts ofanhydrous potassium carbonate, 20 parts of ethyl Z-methylacetoacetate,40 parts of ethanol, and parts of-water is heated under reflux at 101]C. for 5 hours. The mixture is cooled and filtered, and the solidresidue is ,yvashed with water and ethanol. There is thus obtained2-p-chlorophenyl-5,6-dimethyl4-hydroxypyrimidine, M.P. 290-294 C. Amixture of 15 parts of this 4;l1ydroxy compound and 20 parts ofphosphorus oxychloride is heated at C. for 2 hours. The mixture ispoured on to,,ice, and the precipitated solid is collected by filtrationand crystallised from ethanol. There is thus obtained 4 chloroZ-p-chlorophenyl-5,6-dimethylpyrimidine, M.P. 124.5-126I5 C.

EXAMPLE 48 The process described in Example 44 is repeated except that2-p-chlorophenyl-4-methoxy-6-1nethylpyrimidine -is used as startingmaterial in place of 4,6-dimethyl-2-phenylpyrimidine, and thebenzene-soluble and insoiuble mateterials are not separated before thewash with saturated sodium bicarbonate solution. There is thusobtained-diethyl 2-(Z-p-chlorophenyl-4 ethoxypyrimid6-yl)malonate M.P.7l-71.5 C.

The 2 p chlorophenyl 4-methoxy-6-methylpyrimidine used as startingmaterial may be obtained as follows:

5.65 parts of 4-chloro-2-p-chlorophenyl-6-methylpyrimidine are added toa solution of i-12 parts of sodium in 80 parts of methanol, and themixture is heated under reflux for two hours. The methanol isevaporated, the residue is dissolved as far as possible in 40 parts ofhot methanol, and the mixture filtered. The filtrate is cooled and wateris added until crystallisation commences. The mixture is set' asideulitil crystallisation is complete, and is then filtered. There is thusobtained, as solid residue, 2-p-chlorophenyl-4-methoxy 6methylpyrimidine, M.P, 56-57 C.

' EXAMPLE 49 A mixture of 0.7 part of sodium hydride and 5 parts ofdimethyl carbonate is stirred and heated under reflux for ten minutesunder nitrogen. 1.4 parts of2-p-chlorophenyl-4-methoxy-6-methylpyrimidine are theri added and themixture is stirred and refluxed under nitrogen for 18 hours. A mixtureof 10 parts of xylene and 5 parts of dimethyl carbonate is added, andthe mixture is heated and stirred for three hoursQThe mixture is cooledto Cf C. and stirred vigorously while 5 parts of acetic acid are addedas rapidly as possible. The resulting slurry is dis- 5 tributed between100 parts of Water and 70 parts of ether. The organic phase is separatedfrom the mixture, washed with 50fparts of saturated aqueoussodiurnbicarbonate, and evaporated. The residue is crystallised frompetroleum ether (B.P. 6080 C.) (charcoal treatment), and from aqueousmethanol (charcoal treatment); There is thus obtained dimethyl2-(2-p-chlorophenyl-4-methoxypyrimid-6-yl)malonate, M.P.' 83-835 C.

EXAMPLE 50 25 under refiux for 6 hours. After cooling, the mixture isfiltered, both the solid residue and the filtrate (A) being retained.The solid residue is stirred with 50 parts of water for minutes, and themixture is filtered. The solid residue is retained (B).

The filtrate (A) is evaporated to dryness under reduced pressure. 150parts of water are added to the residue, and the mixture is stirred for5 minutes and then filtered. The solid residue is dried, stirred for 5minutes with 50 parts of chloroform, and the mixture is filtered. Thesolid residue is dissolved in a mixture of parts of methanol and 90parts of chloroform. The solution is passed through a column of 130parts of magnesia-silica gel. The column is eluted with 2000 parts of a5:95 v./v. methanolzchloroform mixture. The solvent is evaporated fromthe eluate under reduced pressure. The residual solid is combined withsolid (B) described above and the combined solids are crystallised frommethanol. There is thus obtained methyl 2-p-chlorophenyl 6hydroxypyrimid-4-ylacetate, M.P. 184.5186.5 C.

EXAMPLE 51 Methyl 2-p-chlorophenyl-6-methoxypyrimid-4-ylacetate (M.P.7880 C.) is prepared in a manner similar to that described in Example 11except that methyl 6-chloro-2-pchlorophenylpyrimid-4-ylacetate is usedin place of ethyl 6-chloro-2-p-chlorophenylpyrimid-4-ylacetate.

EXAMPLE 52 A mixture of 100 parts of methyl 2-p-chlorophenyl-6-methoxypyrimid-4-ylacetate and 300 parts of maize starch is granulatedwith a sufficient quantity of 10% w/v starch paste. The granules arepassed through a 20 mesh screen and are then dried at a temperature notexceeding C. The dried granules are then blended with 4 parts ofmagnesium stearate and then compressed into tablets which may containfrom to 250 mgs. of active ingredient. There are thus obtained tabletssuitable for oral use for therapeutic purposes.

Instead of the 100 parts of methyl 2p-chlorophenyl-6-methoxypyrimid-4-ylacetate there may be used 100 parts of2-p-chlorophenyl-6-methoxy-4-methylpyrimid-5-ylacetic acid or 100 partsof diethyl-2-p-chlorophenyl-6-methoxypyrimid-4-ylmalonate, and in asimilar manner there are obtained tablets suitable for oraladministration for therapeutic purposes.

EXAMPLE 5 3 5 parts of methyl 2-p-chlorophenyl-6-methoxy-pyrimid4-ylacetate are added to a stirred mixture of 9 parts of liquid parafiinand 86 parts of soft white paraflin heated at 65 C. The mixture isallowed to cool and stirring is continued until the mixture is cool.There is thus obtained an ointment suitable for topical application fortherapeutic purposes.

EXAMPLE 54 To a stirred mixture of 20 parts of stearic acid, 15 parts ofarachis oil, 5 parts of liquid paraffin and 5 parts of cetostearylalcohol, heated at 65 C., there is added a solution at 60 C. preparedfrom 5 parts of 2-p-chlorophenyl-6-methoxy-4-methylpyrimid-5-ylaceticacid, 2.5 parts of triethanolamine and 53.5 parts of water. Stirring iscontinued after mixing while the temperature is allowed to fall to 40 C.The mixture is then homogenised by passage through a colloid mill. Thereis thus obtained a vanishing cream suitable for topical application fortherapeutic purposes.

The pyrimidine derivatives of this invention possess antiinflammatory,analgesic and antipyretic activity, for example such activity instandard experimental animals (rats or mice), and they may therefore beused in the treatment of man or other host needing such activity. On thebasis of results in standard experimental animals we consider that saidpyrimidine derivatives may be used clinically in man in the formulationsand at the doses indi- 26 cated below, depending upon the clinicaleffect that is desired:

(1) Anti-inflammatory effect Said pyrimidine derivative, for examplemethyl 2-pchlorophenyl-6-methoxypyrimid-4-ylacetate, may be administeredorally in the form of a tablet at a total daily dose of 500 mg. of saidderivative per 70 kg. man. Alternatively, said derivative may beadministered topically in the form of an ointment or cream containing2.5-7.5% by Weight of said derivative, the ointment or cream beingadministered as necessary.

(2) Analgesic effect Said pyrimidine derivative may be administeredorally in the form of a tablet at a total daily dose of 100-600 mg. ofsaid derivative per 70 kg. man.

(3) Antipyretic effect Said pyrimidine derivative may be administeredorally in the form of a tablet at a total daily dose of 100-600 mg. ofsaid derivative per 70 kg. man.

What we claim is:

1. A pyrimidine derivative of the formula:

W N=l= X N Y wherein Y and Z are linked to non-adjacent carbon atoms inthe pyrimidine nucleus;

W stands for hydrogen or straight chain alkyl of not more than threecarbon atoms;

X stands for hydrogen, straight chain alkyl of not more than threecarbon atoms, straight chain alkoxy of not more than three carbon atoms,or a halogen atom;

Y stands for monoh-alogenophenyl, dihalogenophenyl,

lmonohalogenobenzyl, dihalogenobenzyl, trifluoromethylphenyl ortrifluoro methylbenzyl; and

Z stands for CR R R wherein R stands for hydrogen, straight chain alkylof not more than three carbon atoms, or a chlorine or bromine atom, Rstands for hydrogen, straight chain alkyl of not more than three carbonatoms, 'alkoxycarbonyl of not more than three carbon atoms, or achlorine or a bromine atom, and R stands for -CO R or CONHR wherein Rstands for hydrogen, alkyl of not more than three carbon atoms,dialkylaminoalkyl of not more than six carbon atoms, or benzyl, and Rstands for hydrogen, amino, dialkylaminoalkyl of not more than sixcarbon atoms, alkoxycarbonylalkyl of not more than four carbon atoms, orcarboxymethyl,

or the non-toxic pharmaceutically acceptable salts thereof. 2. Acompound as claimed in claim 1 which is diethyl 2-(2-p-chlorophenyl-6-methoxypyrimid-4-y1) malonate.

3. A compound as claimed in claim 1 which is2-pchlorophenyl-6-methoxy-4-methylpyrimid-5-ylacetic acid.

4. A compound as claimed in claim 1 which is methylu-(2-p-chlorophenyl-6-methoxypyrimid-4-yl) propionate.

5. A compound as claimed in claim- 1 which is methyl2-p-chlorophenyl-6-methoxypyrimid-4-ylacetate.

References Cited UNITED STATES PATENTS 3,225,047 12/1965 Partyka260-2564 OTHER REFERENCES Verma et a1., CA. 59, 7522 (1963) ALEX MAZEL,Primary Examiner R. V. RUSH, Assistant Examiner US. Cl. X.R.

